title: Angiotensin II stimulates cardiac fibroblast migration via the differential regulation of matrixins and RECK.
abstract: Sustained induction and activation of matrixins (matrix metalloproteinases or MMPs), and the destruction and deposition of extracellular matrix (ECM), are the hallmarks of cardiac fibrosis. The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) is a unique membrane-anchored endogenous MMP regulator. We hypothesized that elevated angiotensin II (Ang II), which is associated with fibrosis in the heart, differentially regulates MMPs and RECK both in vivo and in vitro. Continuous infusion of Ang II into male C57Bl/6 mice for 2weeks resulted in cardiac fibrosis, with increased expressions of MMPs 2, 7, 9 and 14, and of collagens Ia1 and IIIa1. The expression of RECK, however, was markedly suppressed. These effects were inhibited by co-treatment with the Ang II type 1 receptor (AT1) antagonist losartan. In vitro, Ang II suppressed RECK expression in adult mouse cardiac fibroblasts (CF) via AT1/Nox4-dependent ERK/Sp1 activation, but induced MMPs 2, 14 and 9 via NF-κB, AP-1 and/or Sp1 activation. Further, while forced expression of RECK inhibits, its knockdown potentiates Ang II-induced CF migration. Notably, RECK overexpression reduced Ang II-induced MMPs 2, 9 and 14 activation, but enhanced collagens Ia1 and IIIa1 expression and soluble collagen release. These results demonstrate for the first time that Ang II suppresses RECK, but induces MMPs both in vivo and in vitro, and RECK overexpression blunts Ang II-induced MMP activation and CF migration in vitro. Strategies that upregulate RECK expression in vivo have the potential to attenuate sustained MMP expression, and blunt fibrosis and adverse remodeling in hypertensive heart diseases.
authors.affiliation: Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, USA; Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Jalahalli M
authors.initials: JM
authors.lastname: Siddesha
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.forename: Siva S V P
authors.initials: SS
authors.lastname: Sakamuri
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Jason D
authors.initials: JD
authors.lastname: Gardner
authors.forename: Naveen
authors.initials: N
authors.lastname: Somanna
authors.forename: Chiaki
authors.initials: C
authors.lastname: Takahashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Noda
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D058851:GPI-Linked Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009206:Myocardium / Q000166:cytology*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D058851:GPI-Linked Proteins; D016328:NF-kappa B; C492025:Reck protein, mouse; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1; D000804:Angiotensin II; D003094:Collagen; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D020782:Matrix Metalloproteinases; D053511:Matrix Metalloproteinase 14
keywords: 12-O-tetradecanoylphorbol-13-acetate; 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide; ADAM; AP-1; ARB; AT1; AT2; Adverse remodeling; CF; CMV; CVD; Cardiac fibrosis; DPI; ECM; EGFP; ERK; Elk; Ets-like protein; GAPDH; GFP; GPI; JNK; LV; MAPK; MMP; MOI; MT1-MMP; MTT; NADPH; NADPH oxidase; NF-κB; Nox; Nox4; RECK; ROS; SBP; Sp1; TACE; TIMP; TPA; TPA DNA response element; TRE; UTR; WT; a disintegrin and metalloproteinase domain; activator protein-1; angiotensin II type 1 receptor; angiotensin II type II receptor; angiotensin receptor blockers; c-Jun amino-terminal kinase; cardiac fibroblasts; cardiovascular disease; cytomegalovirus; diphenylene iodonium; enhanced green fluorescent protein; extracellular matrix; extracellular signal-regulated kinase; glyceraldehyde-3-phosphate dehydrogenase; glycophosphatidylinositol; green fluorescent protein; left ventricle; matrix metalloproteinase; membrane type 1-MMP; mitogen-activated protein kinase; multiplicity of infection; nicotinamide adenine dinucleotide phosphate; nuclear factor kappa B; reactive oxygen species; reversion-inducing-cysteine-rich protein with Kazal motifs; shRNA; short hairpin RNA; siMMP; small inhibitory RNA against MMP; specific protein 1; systolic blood pressure; tissue inhibitor of metalloproteinase; tumor necrosis factor, alpha, converting enzyme; untranslated region; wild-type